World Health Organization Classification of Tumours Pathology and ...

acinar pattern. The alveolar and acinarstructures may dilate, producing microcysticand macrocystic patterns.Infrequently, clear cell renal cell carcinomahas a distinct tubular pattern andrarely a pseudopapillary architecture isfocally present.The cytoplasm is commonly filled withlipids and glycogen, which are dissolvedin routine histologic processing, creatinga clear cytoplasm surrounded by a distinctcell membrane. Many tumours containminority populations of cells witheosinophilic cytoplasm; this is particularlycommon in high grade tumours andadjacent to areas with necrosis or haemorrhage.In well preserved preparations, the nucleitend to be round and uniform with finelygranular, evenly distributed chromatin.Depending upon the grade, nucleoli maybe inconspicuous, small, or large andprominent. Very large nuclei lackingnucleoli or bizarre nuclei may occasionallyoccur. A host of unusual histologicfindings are described in clear cell renalcell carcinoma. Sarcomatoid changeoccurs in 5% of tumours and is associatedwith worse prognosis. Some tumourshave central areas of fibromyxoid stroma,areas of calcification or ossification{991}. Most clear cell RCCs have littleassociated inflammatory response; infrequently,an intense lymphocytic or neutrophilicinfiltrate is present.ImmunoprofileClear cell RCCs frequently react withantibodies to brush border antigens, lowmolecular weight cytokeratins, CK8,CK18, CK19, AE1, Cam 5.2 and vimentin{1675,2086,2818,2880}. High molecularweight cytokeratins, including CK14{464}, and 34βE12 are rarely detected.The majority of clear cell RCCs reactpositively for renal cell carcinoma marker{1675}, CD10 {140} and epithelial membraneantigen {776}. MUCΙ and MUC3are consistently expressed {1479}.GradingNuclear grade, after stage, is the mostimportant prognostic feature of clearcell renal cell carcinoma {441,764,815,949,2433,2473,2940}. The prognosticvalue of nuclear grade has beenvalidated in numerous studies over thepast 8 decades. Both 4-tiered and 3-tiered grading systems are in widespreaduse. The 4-tiered nuclear gradingsystem {815} is as follows: Using the 10xobjective, grade 1 cells have smallhyperchromatic nuclei (resemblingmature lymphocytes) with no visiblenucleoli and little detail in the chromatin.Grade 2 cells have finely granular "open"chromatin but inconspicuous nucleoli atthis magnification. For nuclear grade 3,the nucleoli must be easily unequivocallyrecognizable with the 10x objective.Nuclear grade 4 is characterizedby nuclear pleomorphism, hyperchromasiaand single to multiple macronucleoli.Grade is assigned based onthe highest grade present. Scatteredcells may be discounted but if severalcells within a single high power focushave high grade characteristics, thenthe tumour should be graded accordingly.Genetic susceptibilityClear cell renal cell carcinoma constitutesa typical manifestation of vonHippel-Lindau disease (VHL) but mayalso occur in other familial renal cell cancersyndromes.Somatic geneticsAlthough most clear cell RCCs are notrelated to von Hippel Lindau disease, 3pdeletions have been described in thevast majority of sporadic clear cell renalcell carcinoma by conventional cytogenetic,FISH, LOH and CGH analyses{1372,1754,1760,1786,2109,2614,2690,2691,2723,2925}. At least 3 separateregions on chromosome 3p have beenimplicated by LOH studies as relevant forsporadic renal cell carcinoma: one coincidentwith the von Hippel-Lindau (VHL)disease gene locus at 3p25-26{1445,2400}, one at 3p21-22 {2689} andone at 3p13-14 {2721}, which includesthe chromosomal translocation point infamilial human renal cell carcinoma.These data suggest involvement of multipleloci on chromosome 3 in renal cancerdevelopment {474,2686}.Mutations of the VHL gene have beendescribed in 34-56% of sporadic clearcell RCC {307,792,897,2342,2400,2810}.DNA methylation was observed in 19% ofclear cell renal cell carcinomas {1082}.Therefore, somatic inactivation of theVHL gene may occur by allelic deletion,mutation, or epigenetic silencing in 70%or more {897,1082,1445,2342}. Thesedata suggest that the VHL gene is themost likely candidate for a tumour suppressorgene in sporadic clear cell RCC.ABFig. 1.18 A VHL, renal carcinoma. Note clear cells and cysts. B Clear cell renal cell carcinoma. Typical alveolar arrangement of cells.24 Tumours of the kidney